The long-acting diuretic chlorthalidone has been known for decades as an effective treatment to lower elevated arterial blood pressure (arterial hypertension or hypertension). The compound received U.S. Pat. No. 3,055,904, which disclosed a dosage range of 50 mg to 200 mg orally one to three times a day or 100 mg every second day. U.S. Pat. No. 5,948,799 discloses a typical range of chlorthalidone of 6.25-200 mg daily and a preferred range of 12.5 to 100 mg daily for use in the treatment of non-ischemic congestive heart failure in combination with amlodipine and/or digoxin; this patent does not address the treatment of hypertension. In addition, the study supporting said patent involved patients receiving amlodipine, almost all of whom were concomitantly receiving digoxin, and both amlodipine and digoxin are known to have diuretic activity.
Chlorthalidone has been chemically described as: benzenesulfonamide, 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1yl) or 2-chloro-5-(1-hydroxy-3-oxo-1,2-dihydroisoindol-1-yl)-benzenesulfonamide.
The U.S. Food and Drug Administration's (FDA) approved starting dose for hypertension for chlorthalidone is 25 mg daily; this dose is available in the U.S. as an unscored tablet. In the European Union, chlorthalidone is available as a 50 mg scored tablet.
Hypertension is widely acknowledged to be one of the most widespread of all illnesses. There are about 60 million cases of hypertension in the U.S. It is believed that approximately ⅓ of all patients with hypertension in the U.S. are adequately treated, ⅓ are treated but not adequately, and ⅓ are not treated.
The invention is timely because the anomalous position of chlorthalidone in hypertension treatment has led to a need for non-obvious doses of this product to be brought to market. On the one hand, chlorthalidone is widely acknowledged to be the diuretic best documented to provide clinically significant benefits in terms of health outcomes. On the other hand, relatively few prescriptions for chlorthalidone are written in the U.S. It is believed that the lack of appropriate low doses helps explain the lack of medical interest in this drug. The following discussion summarizes how this situation has developed and why there is a medical need for the invention.
Chlorthalidone was extensively studied versus another diuretic, hydrochlorothiazide (HCTZ), in the 1970's, in the Multiple Risk Factor Intervention Trial, a National Institute of Health (NIH)-sponsored study. The investigators concluded that chlorthalidone appeared potentially superior to HCTZ. Subsequently, NIH sponsored four (4) large-scale health outcomes utilizing a diuretic. The diuretic chosen each time was chlorthalidone. The four studies were the Treatment of Mild Hypertension Study (TOMHS), Hypertension Detection and Follow-Up Program (HDFP), Systolic Hypertension in the Elderly Program (SHEP), and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study. Of the above studies, the last two utilized starting doses of 12.5 mg of chlorthalidone. However, the patient populations in these two studies were not typical hypertension patients. In SHEP, all patients were at least sixty years old and had systolic hypertension. In ALLHAT, patients had more risk factors than other patients, and there was no placebo group, so that efficacy of the 12.5 mg dose vs. placebo was not tested. In addition, in ALLHAT, all patients were at least 55 years old and the average was 67; thus its results were geared toward the elderly. Dose escalation was the general strategy for SHEP and ALLHAT as needed. Smaller studies of the 12.5 mg dose have been performed, all with trends toward efficacy of that dose in treating hypertension.
At the same time as the above studies were being conducted, HCTZ became the prevalent treatment for hypertension when a diuretic was utilized in the U.S. A commonly provided reason for this is that chlorthalidone was not produced in a dose low enough to avoid metabolic side effects such as hypokalemia and diabetes, whereas HCTZ was developed in a dose as low as 12.5 mg in 1997. It is thus an intention of the inventor to bring to market novel doses of chlorthalidone to treat hypertension that have not been disclosed, and that are freer of side effects than existing chlorthalidone doses, while still providing anti-hypertensive benefits.
Doses of chlorthalidone below 12.5 mg daily have not been studied for the treatment of hypertension. Carter et al., has suggested, without compelling evidence, that 6.25 mg daily may be an appropriate starting dose for elderly patients with hypertension. Carter, B. L., Ernst, M. E., Cohen, J. D., “Hydrochlorothiazide versus chorthalidone: evidence supporting their interchangeability.” Hypertension 43 (2004): 4-9 (hereafter “Carter”).
The failure of Carter to propose a 6.25 mg chlorthalidone dose for hypertension other than for the elderly suggests that efficacy at this dose other than in the elderly (excluding the frail, renally-impaired, or pediatric populations, etc.) would be unexpected. A close reading of the article does not clearly support even the recommendation for the ultra-low dose of 6.25 in the elderly, as the author admits that “the more recent recommendations (are) that the 2 drugs are equipotent,” and the author offers 12.5 mg as the starting dose of HCTZ for the elderly. It is well recognized that 6.25 mg of HCTZ is not a predictably effective dose for hypertension.
Evidence of the importance of a novel ultra-low dose of chlorthalidone to treat hypertension may be seen in the study of Materson et al., which found that the incidence of hypokalemia at 12.5 mg of chlorthalidone daily was 45% at 12.5 mg, 35% at 25 mg, 41% at 50 mg, and 42% with 75 mg, all doses once daily. Materson, B. J., Oster, J. R., Michael, U. F., Bolton, S. M., Burton, Z. C., Stambaugh, J. E., Morledge, J. M., “Dose Response to Chlorthalidone In Patients With Mild Hypertension.” Clinical Pharmacology and Therapeutics Vol. 24, No. 2 (1978): 192-198. The failure of this study to demonstrate a dose relationship of chlorthalidone with regard to hypokalemia suggests the need for lower doses that retain adequate anti-hypertensive effect.
All doses referred to herein are oral doses.
Chlorthalidone, as with other anti-hypertensive agents, is taught to be started at the lowest dose appropriate and then for the dose to be increased as needed. In the case of the Carter article, 6.25 mg is disclosed as a starting dose for the elderly.
The dosages of chlorthalidone referred to herein assume that the formulation does not contain a solubility enhancer. Poly(vinyl pyrrolidone), otherwise known as PVP, has been used in the marketed product Thalitone® to provide greater bioavailability than the standard Hygroton® brand provided. All formulations described herein relate to standard formulations that have immediate release characteristics and do not utilize PVP or other solubility or absorption modifiers.